Regulation of the immune system in mammals is complicated and involves many pathways. Various factors can cause a modulation in the immune system, for example, viral infections, bacterial infections, parasitic infections, introduction of drugs or other foreign substances into an individual, transformation of cells into cancerous growths within the individual, and development of autoimmune reactions within the individual. Although the immune system is very complex, it can be divided loosely into three major systems: humoral immunity, cellular immunity, and innate immunity. An important component of the humoral immunity is the B lymphocyte; an important component of the cellular immunity is the T lymphocyte; and an important component of the innate immune system is the NK cell.
The predominant function of B cells is the production of specific antibodies to foreign antigens. Following the interactions of surface receptors with foreign antigens and in the presence of T cells, B cells will differentiate into plasma cells which are the producers of circulating antibodies.
Antigen receptors used by T cells (TCR) are composed of a set of invariant chains (collectively referred to as the CD3 complex) and polymorphic chains divided into constant and variable portions. The T lymphocytes are divided mainly into two subpopulations: the helper T lymphocytes (CD3+CD4+) and the cytotoxic T lymphocytes (CD3+CD8+). The major role of helper T cells is to secrete cytokines that will stimulate other cells to accomplish their functions. The cytotoxic T cells are capable of killing other cells expressing foreign antigens presented in association with major histocompatibility complex I (MHC I) glycoproteins on “accessory cells” such as macrophages.
Compounds have been identified that modulate the immune system. For example, cyclosporin is used to suppress T cells in organ transplantations to prevent rejection of the donor organ by the recipient. Lipopolysaccharides (LPS) have been found to stimulate B cells. Levamisole, an anti-helminth agent, has been disclosed to promote phagocytic activity of polymorphonuclear leukocytes. See, for example, Forum on Immunotherapy “The History and Development of Levaminsole”, edited by D. A. Willoughby and Clive Wood, Vol. 1 (1):2-10 (1977). 6(5)-phenanthridinone has also been disclosed to inhibit lymphocyte proliferation and depresses induction of CTL cells. Weltin D., et al. Int. J. Immunopharmac., 17(4): 265-271 (1995).
The ability to immunomodulate different populations of cells or even different branches of the immune system can be useful for treating various types of diseases or ailments. Since NK cells are widely known to target tumor cells and virally infected cells, it would be highly beneficial to increase or stimulate NK cells to treat an individual with cancer or with a viral infection(s). In addition to modulating activity or population of cell types, it would also be highly beneficial if a compound could immunomodulate cytokine production, for example, an anti-viral cytokine such as interferon-γ. Further, immunomodulating immune responses such that they would favor a cellular immune response over a humoral immune response could also be beneficial for treating ailments and disease for which cellular immune responses are more effective. Likewise, a shift in immune response from Th2 to Th1 response may be beneficial in avoiding undesired inflammatory responses that may otherwise be encountered during a Th2 response.
There exists a need for compounds that can immunomodulate the cellular, humoral, and innate immune response. The invention disclosed herein fulfulls this need.
All patents, publications, and references referred to herein are hereby incorporated by reference in their entirety.